Opti-Med: the effectiveness of optimised clinical medication reviews in older people with 'geriatric giants' in general practice; study protocol of a cluster randomised controlled trial.
Inappropriate drug use has been identified as one of the most important problems affecting the quality of care in older people. Inappropriate drug use may increase the risk of the occurrence of 'geriatric giants' such as immobility, instability, incontinence and cognitive impairment. There are indications that clinical medication reviews (CMR) can reduce inappropriate drug use. However, CMRs have not yet been implemented at a large scale in primary care. An innovative medication review program in primary care will be developed which tackles the most important obstacles for a large scale implementation of CMRs. The aim of this study is to assess whether this CMR program is (cost-) effective compared with usual general practice care for older patients with geriatric symptoms with regard to quality of life and geriatric symptoms. A cluster randomised controlled trial will be performed in 20 Dutch general practices including 500 patients. Patients of 65 years and older are eligible if they newly present with pre-specified geriatric symptoms in general practice and chronic use of at least one prescribed drug. GP practices will be stratified by practice size and randomly allocated to control (n = 10) or intervention group (n = 10). The intervention consists of CMRs which will be facilitated and prepared by an expert team consisting of a GP and a pharmacist. Primary outcome measures are patient's quality of life and the presence of self-reported geriatric symptoms during a follow-up period of 6 months. Secondary outcomes are costs of healthcare utilisation, feasibility, number of drug related problems, medication adherence and satisfaction with medication. This study is expected to add evidence on the (cost-) effectiveness of an optimally facilitated, prepared and structured CMR in comparison with usual care in older patients who present a geriatric symptom to their GP. The strength of this study is that it will be conducted in daily clinical practice. This improves the possibilities to implement the CMRs in the primary care setting on a large scale. Netherlands Trial register: NTR4264.


Anti-PD-1/L1 lead-in before MAPK inhibitor combination maximizes antitumor immunity and efficacy.
Rationally sequencing and combining PD-1/L1-and MAPK-targeted therapies may overcome innate and acquired resistance. Since increased clinical benefit of MAPK inhibitors (MAPKi) is associated with previous immune checkpoint therapy, we compare the efficacies of sequential and/or combinatorial regimens in subcutaneous murine models of melanoma driven by BrafV600, Nras, or Nf1 mutations as well as colorectal and pancreatic carcinoma driven by KrasG12C. Anti-PD-1/L1 lead-in preceding MAPKi combination optimizes response durability by promoting pro-inflammatory polarization of macrophages and clonal expansion of interferon-γhi, and CD8+ cytotoxic and proliferative (versus CD4+ regulatory) T cells that highly express activation genes. Since therapeutic resistance of melanoma brain metastasis (MBM) limits patient survival, we demonstrate that sequencing anti-PD-1/L1 therapy before MAPKi combination suppresses MBM and improves mouse survival with robust T cell clonal expansion in both intracranial and extracranial metastatic sites. We propose clinically testing brief anti-PD-1/L1 (± anti-CTLA-4) dosing before MAPKi co-treatment to suppress therapeutic resistance.


Calcitonin, katacalcin, and calcitonin gene-related peptide in the human prostate. An immunocytochemical and immunoelectron microscopic study.
We recently described for the first time the presence of calcitonin immunoreactivity (CTIR) in a subpopulation of prostatic and urethral endocrine-paracrine (EP) cells. We now further evaluate the distribution of the CTIR cell, characterize the coexistence of serotonin and calcitonin, and for the first time describe the coexpression of calcitonin and other calcitonin gene family peptides (calcitonin gene-related peptide and katacalcin) in the CTIR cell. Finally, the morphological ultrastructure of the secretory granule of the CTIR cell is analyzed. The finding of multiple calcitonin gene family peptides in prostatic and urethral EP cells and the specific localization of calcitonin to secretory granules strongly suggest that the calcitonin gene is expressed in this region and the products stored in the EP cells. The relatively high levels of calcitonin reported in the semen and the dendritic and nondendritic morphological features of the CTIR cell, respectively, suggest a lumencrine (exocrine), paracrine, and possibly endocrine role for calcitonin. The production of calcitonin and related peptides by the prostate may have implications in various pathologic processes of the prostate.


Potential impact of gene regulatory mechanisms on the evolution of multicellularity in the volvocine algae.
A fundamental question in biology is how multicellular organisms can arise from their single-celled precursors. The evolution of multicellularity requires the adoption of new traits in unicellular ancestors that allows the generation of form by, for example, increasing the size and developing new cell types. But what are the genetic, cellular and biochemical bases underlying the evolution of multicellularity? Recent advances in evolutionary developmental biology suggest that the regulation of gene expression by cis-regulatory factors, gene duplication and alternative splicing contribute to phenotypic evolution. These mechanisms enable different degrees of phenotypic divergence and complexity with variation in traits from genomes with similar gene contents. In addition, signaling pathways specific to cell types are developed to guarantee the modulation of cellular and developmental processes matched to the cell types as well as the maintenance of multicellularity.


Clinical fit of four-unit zirconia posterior fixed dental prostheses.
The objective of this clinical study was to assess the internal and marginal accuracy of computer-aided design/computer-aided manufacturing (CAD/CAM)-generated four-unit all-ceramic posterior fixed dental prostheses (FDPs). The data were compared with the results of three-unit metal-ceramic and all-ceramic FDPs that were obtained in a previous study. Twenty-four patients were provided with all-ceramic posterior four-unit FDPs made from semisintered blank zirconia material. Prior to definitive insertion the accuracy was evaluated using a replica technique with a light body silicone that was stabilized with a heavy body material. The replica samples were examined using microscopy. The median marginal gap of the 24 four-unit FDPs was 77 mum. The median gap widths were 87 mum at the midaxial wall, 167 mum at the axio-occlusal transition of the abutments, and 170 mum at centro-occlusal location. Although the marginal accuracy of the four-unit FDPs differed significantly from that of the three-unit metal-ceramic FDPs (median 54 mum), the values obtained were clinically satisfactory and showed that semisintered zirconia blanks could be used for the fabrication of four-unit FDPs.


Gastric electric stimulation for the treatment of gastroparesis.
Gastric electric stimulation is an emerging therapy for refractory gastroparesis. Several methods have been used to electrically stimulate the stomach. Initial studies used gastric electrical pacing, which entrains and paces the gastric slow waves at a slightly higher rate than the patient's normal myoelectric frequency of 3 cycles per minute (cpm). The technique currently practiced uses high-frequency, low-energy stimulation at four times the basal rate (12 cpm). Results from published studies with high-frequency stimulation reveal an improvement in symptoms, primarily of nausea and vomiting, and primarily in patients with diabetic gastroparesis, with only a modest change in gastric emptying. As treatment with gastric electric stimulation evolves, further delineation of its overall effectiveness, the type of patient that will likely respond, optimal electrode placement(s), and stimulus parameters should be explored.


Catel-Manzke syndrome without cleft palate: a case report.
We report a boy who presented with mild facial dysmorphism, pectus excavatum, bilateral brachydactyly and ulnar deviation of both index fingers. Radiological examination of the hands showed abnormal proximal phalanges of the second digits. This case differs from the classical Catel-Manzke syndrome in having isolated hand malformations without any other malformations such as cleft palate or cardiac abnormalities.


Video-assisted thoracoscopic cardiac denervation of refractory ventricular arrhythmias and electrical storms: a single-center series.
The combined treatment of beta-blockers with ablation and Implanted cardioverter defibrillation therapy, continues to be the mainstay treatment for ventricular arrhythmias (VAs). Despite treatment, some patients remain refractory. Recent studies have shown success rates using video-assisted thoracoscopic (VATS) cardiac denervation as an effective therapeutic option for these patients. During a period of three years, from 2015 through 2017, twenty patients (N = 20) failed traditional medical and interventional treatment for the management of ventricular arrhythmias and electrical storms. After remaining refractory, the patients were referred to our thoracic surgery department for a VATS based treatment. The patients all had ventricular arrhythmias and electrical storms secondary to different cardiomyopathies. The patients were refractory to combined medical (beta-blockers), Implanted Cardioverter defibrillation (ICD) and ablation therapy. All twenty patients agreed to surgery and were taken to cardiac denervation using a bilateral VATS approach by two thoracic surgeons at a single Cardiothoracic center. During the month prior to bilateral VATS denervation a combined total of twenty-nine (N = 29) ICD shocks were registered in addition to six (N = 6) cases of electrical storms averaging three (N = 3) shocks per day. Mean shocks per patient was 2.3. During the first three months following VATS, the patients had a 90% (N = 18/20) total resolution of ICD registered shocks, a 100% (N = 6/6) resolution of electrical storms, and a 92% (N = 11/12) resolution of shocks in patients having previous ablation therapy. No complications were documented following surgery except for one case of pneumothorax as a result of the procedure, and there were no peri-operative mortalities. Bilateral thoracoscopic cardiac denervation can be a safe and seemingly effective therapeutic option for patients presenting with life-threatening refractory ventricular arrhythmias and electrical storms in a variety of cardiomyopathies including Chagas disease.


Treatment of hormone-refractory breast cancer: apoptosis and regression of human tumors implanted in mice.
Following surgery, the hormone dependence of breast tumors is exploited for therapy using antagonists such as tamoxifen, although occasional hormone-resistant clones do appear. Another chemotherapeutic strategy uses microtubule inhibitors such as taxanes. Unfortunately, these agents elicit toxicities such as leukocytopenia, diarrhea, alopecia, and peripheral neuropathies and are also associated with the emergence of drug resistance. We have previously described a tubulin-binding, natural compound, noscapine, that was nontoxic and triggered apoptosis in many cancer types albeit at 10 mumol/L or higher concentrations depending on the cell type. We now show that a synthetic analogue of noscapine, 9-bromonoscapine, is approximately 10-fold to 15-fold more potent than noscapine in inhibiting cell proliferation and induces apoptosis following G2-M arrest in hormone-insensitive human breast cancers (MDA-MB-231). Furthermore, a clear loss of mitochondrial membrane potential, release of cytochrome c, activation of the terminal caspase-3, and the cleavage of its substrates such as poly(ADP-ribose) polymerase, suggest an intrinsic apoptotic mechanism. Taken together, these data point to a mitochondrially mediated apoptosis of hormone-insensitive breast cancer cells. Human tumor xenografts in nude mice showed significant tumor volume reduction and a surprising increase in longevity without signs of obvious toxicity. Thus, our data provide compelling evidence that 9-bromonoscapine can be useful for the therapy of hormone-refractory breast cancer.


Establishment of an Ex Vivo Lung Perfusion Rat Model for Translational Insights in Lung Transplantation.
Since the establishment of lung transplantation as a therapeutic strategy for advanced lung diseases, the scientific community is faced with the problem of a low number of lungs considered viable for the donation process. In recent decades, however, this scenario has been positively changed, given the development of ex vivo lung perfusion (EVLP) as a strategy for evaluating and reconditioning marginal lungs. The establishment of EVLP in large transplant centers has favored an increase in the number of lung transplants, both by increasing the diagnostic accuracy of lung function and by constituting an effective platform for the reconditioning of lung grafts. In this context, faced with ethical and logistical issues, as well as in the study of immunological factors associated with lung transplantation, the development of rodent EVLP models has become important, given their reliability, the possibility of genetic manipulation, and lower costs. This paper describes a protocol for establishing a rat EVLP model and shows the inflammatory profile associated with the perfused lungs. This will help propagate knowledge about the rat EVLP model, promoting our understanding of the biological responses associated with that revolutionary technique.


Identification and characterization of aging/senescence-induced genes in osteosarcoma and predicting clinical prognosis.
Aging is an influential risk factor for progression of both degenerative and oncological diseases of the bone. Osteosarcoma, considered the most common primary mesenchymal tumor of the bone, is a worldwide disease with poor 5-year survival. This study investigated the role of aging-/senescence-induced genes (ASIGs) in contributing to osteosarcoma diagnosis, prognosis, and therapeutic agent prediction. Therapeutically Applicable Research to Generate Effective Treatments (TARGET), Gene Expression Omnibus (GEO), and The Cancer Genome Atlas (TCGA) were used to collect relevant gene expression and clinical data of osteosarcoma and paracancerous tissues. Patients were clustered by consensus using prognosis-related ASIGs. ssGSEA, ESTIMATE, and TIMER were used to determine the tumor immune microenvironment (TIME) of subgroups. Functional analysis of differentially expressed genes between subgroups, including Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and gene set variation analyses (GSVAs), was performed to clarify functional status. Prognostic risk models were constructed by univariate Cox regression and least absolute shrinkage and selection operator (LASSO) regression. SCISSOR was used to identify relevant cells in osteosarcoma single-cell data for different risk groups. The effect of immunotherapy was predicted based on TIDE scores and chemotherapy drug sensitivity using CTRP and PRISM. Three molecular subgroups were identified based on prognostic differentially expressed ASIGs. Immunological infiltration levels of the three groups differed significantly. Based on GO and KEGG analyses, differentially expressed genes between the three subgroups mainly relate to immune and aging regulation pathways; GSVA showed substantial variations in multiple Hallmark pathways among the subgroups. The ASIG risk score built based on differentially expressed genes can predict patient survival and immune status. We also developed a nomogram graph to accurately predict prognosis in combination with clinical characteristics. The correlation between the immune activation profile of patients and the risk score is discussed. Through single-cell analysis of the tumor microenvironment, we identified distinct risk-group-associated cells with significant differences in immune signaling pathways. Immunotherapeutic efficacy and chemotherapeutic agent screening were evaluated based on risk score. Aging-related prognostic genes can distinguish osteosarcoma molecular subgroups. Our novel aging-associated gene signature risk score can be used to predict the osteosarcoma immune landscape and prognosis. Moreover, the risk score correlates with the TIME and provides a reference for immunotherapy and chemotherapy in terms of osteosarcoma.


The effect of prostacyclin and its analogues on cysteamine-induced duodenal ulceration of rats.
The effect of prostacyclin and its analogues--6-keto-prostaglandin-F1 alpha and 6-beta-prostaglandin-I1--on cysteamine-induced duodenal ulceration of rats was investigated. It seems that neither prostacyclin, nor its analogues have anti-ulcerogenic effect in this model.


Biofilm in water pipelines; a potential source for off-flavours in the drinking water.
Volatile organic compounds (VOC) are identified in natural biofilm established in plastic pipes used at the drinking water supply. Odour potent VOCs such as ectocarpene, dictyopterene A and C', geosmin, beta-ionone, 6-methyl-5-hepten-2-one, menthol and menthone were prominent compounds in biofilm in the distribution network and at raw water test sites, and are associated with algae and cyanobacteria present in the raw water source.


Functional reassessment of PAX6 single nucleotide variants by in vitro splicing assay.
Nucleotide variants that disrupt normal splicing might be the cause of a large number of diseases. Nevertheless, because of the complexity of splicing regulation, it is not always possible to accurately predict the effect of nucleotide sequence changes on splicing events and mRNA structure. Thereby, a number of newly identified nucleotide variants are falsely classified as VUS (a variant of uncertain significance). In the present study we used the minigene assay to analyze the functional consequences of six intronic (c.142-5T>G, c.142-14C>G, c.142-64A>C, c.141+4A>G, c.1032+ 6T>G, c.682+4delA), one missense (c.140A>G) and one synonymous (c.174C>T) variants in the PAX6 gene found in patients with congenital aniridia. We revealed that all except one (c.142-64A>C) variants lead to the disruption of normal splicing patterns resulting in premature termination codon formation followed by mRNA degradation through the nonsense mediated decay pathway. This produces a null allele of the PAX6 gene. That allowed us to reclassify the analyzed variants as loss-of-function and to establish their functional role.


Current first- and second-line treatment options in acute promyelocytic leukemia.
Outcome of acute promyelocytic leukemia (APL) has remarkably improved during the last 30 years, especially after the identification of PML-RARA oncogene as a key in the pathogenesis of APL and all-trans retinoic acid as therapeutic agent. Arsenic trioxide has been recently demonstrated to be the most effective single antileukemic agent and it has also showed synergistic action when combined with all-trans retinoic acid, decreasing relapse rate especially in low/intermediate-risk settings. Therapeutic advances led to complete remission rates of more than 90%, modifying disease history. In relapse setting, arsenic trioxide-based regimens showed efficacy for the achievement of second molecular complete remission. The most challenging issue in APL management remains the significant early deaths rate, nowadays the principal reason for treatment failure.


Systems biology at the Institute for Systems Biology.
Systems biology represents an experimental approach to biology that attempts to study biological systems in a holistic rather than an atomistic manner. Ideally this involves gathering dynamic and global data sets as well as phenotypic data from different levels of the biological information hierarchy, integrating them and modeling them graphically and/or mathematically to generate mechanistic explanations for the emergent systems properties. This requires that the biological frontiers drive the development of new measurement and visualization technologies and the pioneering of new computational and mathematical tools-all of which requires a cross-disciplinary environment composed of biologists, chemists, computer scientists, engineers, mathematicians, physicists, and physicians speaking common discipline languages. The Institute for Systems Biology has aspired to pioneer and seamlessly integrate each of these concepts.


MicroRNA-145 targets TRIM2 and exerts tumor-suppressing functions in epithelial ovarian cancer.
Epithelial ovarian cancer (EOC) is one of the most common cancers in women worldwide but relatively little is known about its molecular pathogenesis. MicroRNAs, which regulate gene expression post-transcriptionally, have emerged as key players in tumorigenesis. The present study aims to investigate the dysregulation of miR-145 in EOC. miRNA expression was assessed in EOC tissues and cell lines by quantitative reverse transcription (RT)-PCR. Xenograft mouse model was used for evaluation of the effect of miR-145 on tumor growth. Cell proliferation, colony formation assays, invasion assay, flow cytometry, Western blot and gene expression analysis were used for identification of the functional role of miR-145 in EOC cells. Luciferase reporter assay was used to confirm the interaction between miR-145 and its target mRNA 3'-UTR. miR-145 expression was downregulated in EOC tissues and cell lines as compared with normal ovarian tissues. Transfection of miR-145 agomiR significantly inhibited the proliferation, colony forming ability, invasiveness and in vivo tumorigenicity of EOC cells. Transfection of agomiR-145 into EOC cells also markedly induced apoptosis. Furthermore, computational algorithm combined with luciferase reporter assays identified TRIM2 as the direct target of miR-145 in EOC cells. To this end, agomiR-145 downregulated TRIM2 to derepress Bim (a pro-apoptotic Bcl-2 family member degraded by TRIM2). These data confirmed the tumor-suppressing function of miR-145 in EOC and identified TRIM2 as a new miR-145 target. In vivo delivery of agomiR-145 might be a feasible approach for miRNA-directed cancer therapy.


An improved bio-inspired algorithm for the directed shortest path problem.
Because most networks are intrinsically directed, the directed shortest path problem has been one of the fundamental issues in network optimization. In this paper, a novel algorithm for finding the shortest path in directed networks is proposed. It extends a bio-inspired path finding model of Physarum polycephalum, which is designed only for undirected networks, by adopting analog circuit analysis. Illustrative examples are given to show the effectiveness of the proposed algorithm in finding the directed shortest path.


MARIHUANA ACTIVITY OF CANNABINOL.
Cannabinol, generally believed to be an inert component of hemp oil, is shown to have marihuana activity. The significance of this observation with regard to the relationship between structure and mamactivity in the class of cannabinols is discussed.


Cryo-Electron Microscopy Structure of an Acinetobacter baumannii Multidrug Efflux Pump.
Resistance-nodulation-cell division multidrug efflux pumps are membrane proteins that catalyze the export of drugs and toxic compounds out of bacterial cells. Within the hydrophobe-amphiphile subfamily, these multidrug-resistant proteins form trimeric efflux pumps. The drug efflux process is energized by the influx of protons. Here, we use single-particle cryo-electron microscopy to elucidate the structure of the Acinetobacter baumannii AdeB multidrug efflux pump embedded in lipidic nanodiscs to a resolution of 2.98 Å. We found that each AdeB molecule within the trimer preferentially takes the resting conformational state in the absence of substrates. We propose that proton influx and drug efflux are synchronized and coordinated within the transport cycle.IMPORTANCEAcinetobacter baumannii is a successful human pathogen which has emerged as one of the most problematic and highly antibiotic-resistant Gram-negative bacteria worldwide. Multidrug efflux is a major mechanism that A. baumannii uses to counteract the action of multiple classes of antibiotics, such as β-lactams, tetracyclines, fluoroquinolones, and aminoglycosides. Here, we report a cryo-electron microscopy (cryo-EM) structure of the prevalent A. baumannii AdeB multidrug efflux pump, which indicates a plausible pathway for multidrug extrusion. Overall, our data suggest a mechanism for energy coupling that powers up this membrane protein to export antibiotics from bacterial cells. Our studies will ultimately inform an era in structure-guided drug design to combat multidrug resistance in these Gram-negative pathogens.


Mining Database to Identify Aging-Related Molecular Subtype and Prognostic Signature in Lung Adenocarcinoma.
Lung cancer is emerging as one of most deadly diseases, and the mortality rate was still high with 5-year overall survival rate less than 20%. Aging is referred as protumorigenic state, and it plays a significant role in cancer development. Molecular subtype of lung cancer was identified by consensus cluster analysis. Prognostic signature was constructed using LASSO cox regression analysis. CeRNA network was constructed to explore lncRNA-miRNA-mRNA regulatory axis. A total of 27 differentially expressed aging-related genes (ARGs) were obtained in LUAD. Three clusters of TCGA-LUAD patients with significant difference in prognosis, immune infiltration, chemotherapy, and targeted therapy were identified. We also developed an aging-related prognostic signature that had a better performance in predicting the1-year, 3-year, and 5-year overall survival of LUAD. Further analysis suggested a significant correlation between prognostic signature gene expression and clinical stage, immune infiltration, tumor mutation burden, microsatellite instability, and drug sensitivity. We also identified the lncRNA UCA1/miR-143-3p/CDK1 regulatory axis in LUAD. Our study identified three clusters of TCGA-LUAD patients with significant difference in prognosis, immune infiltration, chemotherapy, and targeted therapy. We also developed an aging-related prognostic signature that had a good performance in the prognosis of LUAD.


Monoclonal antibodies directed against the Epstein-Barr virus-encoded nuclear antigen 1 (EBNA1): immunohistologic detection of EBNA1 in the malignant cells of Hodgkin's disease.
Monoclonal antibodies directed against the Epstein-Barr virus nuclear protein 1 (EBNA1) were used to examine conventional paraffin sections from a series of EBV-associated lymphoproliferative disorders by immunohistochemistry. The presence of latent EBV infection in tumor cells was determined by in situ hybridization for the Epstein-Barr virus early RNAs (EBERs). Of those EBER-positive cases a total of 28 of 40 cases of Hodgkin's disease, 3 of 3 cases of Burkitt's lymphoma, and 8 of 8 cases of human immunodeficiency virus-associated cerebral B-cell lymphoma expressed detectable amounts of EBNA1. In the positive cases, expression was confined to the tumor cells. No reactivity was detected in EBV-negative cases of the above tumors or in 8 cases of EBV-negative cases of large cell anaplastic non-Hodgkin lymphoma. This report provides the first unequivocal evidence for the expression of the EBNA1 protein in the tumor cells of Hodgkin's disease and validates an important reagent with which to analyze the role of EBV in various virus-associated malignancies.


Student Perceptions of the Professional Behavior of Faculty Physicians.
This study was conducted to obtain a baseline understanding of the professional behavior of clinical faculty physicians from the medical students' perspective. Students completed a professionalism evaluation of supervising faculty at the end of each required third-year clerkship over a one year period. Results were analyzed by specific behaviors and across clerkships. Differences were noted in the frequency of the types of problems seen, and varied by clerkship discipline. The most common transgressions of professional behavior reported were the use of derogatory language towards other services or patients and the disrespectful treatment of others. Our study served to provide objective feedback to the faculty about student perceptions of faculty as role models for professionalism while on clinical rotations.


Cervical pedicle subtraction osteotomy for fixed flexion deformities.
Flexion deformities of the cervical spine are multiplanar surgical challenges. This article describes a technical modification during the osteotomy that protects the cervical cord and exiting nerve roots while removing the maximal amount of bone for the osteotomy in the safest fashion.


Pulmonary function test outcomes in healthy Navajo Native American adolescents.
Prediction equations for estimating lung volumes have been determined for Caucasians, African-Americans, and Mexican-Americans. These separate equations were determined because of differences in thoracic morphology between people of various racial groups, making it impossible to use one prediction formula to accurately estimate lung volumes for all individuals. One hundred ninety-one adolescent Navajo children (males, n = 110; females, n = 81) between 11 and 18 yr of age volunteered for the study and underwent a series of pulmonary function tests (PFT). New pulmonary function prediction equations for Navajo youth were generated for estimating pulmonary volumes and capacities that more accurately predict expected PFT outcomes than formulas in common use for Caucasian, Mexican-American, or African-American youth.


Propofol reduces spinal motor neuron excitability in humans.
We investigated in humans whether changes in spinal motor neuron excitability correlate with the predicted propofol concentration (Cpt) achieved by a target-controlled infusion system. Propofol suppressed F-wave persistence in a Cpt-dependent manner, indicating that propofol depresses spinal motor neuron excitability at clinically relevant concentrations.


Alpha-2c-adrenergic receptors contribute to basal nasal patency in the anesthetized cat.
Nasal congestion is the most troublesome symptom associated with a variety of upper airway diseases, including allergic rhinitis and the common cold. A better understanding of the mechanisms that regulate nasal cavity caliber may engender the development of novel treatment strategies. It is well accepted that alpha-adrenergic (both alpha(1) and alpha(2)) mechanisms play a fundamental role in the control and maintenance of basal nasal patency. JP-1302 is a selective alpha(2c)-subtype antagonist that has been recently described in the scientific literature. Thus, we sought to examine the potential effects of this new pharmacological tool on basal nasal patency. Using acoustic rhinometry, we studied the activity of the selective alpha(2c)-antagonist JP-1302 on nasal cavity volumes in an anesthetized cat. Cumulative concentrations of JP-1302 were applied directly into the right nasal cavity. Changes in the nasal cavity geometry of the drug-treated naris relative to the untreated left nasal cavity were determined. In separate studies, the nonselective alpha(2)-antagonist yohimbine and the nonselective alpha(1)-antagonist prazosin were run as comparators. Systolic blood pressure was measured at the hind leg, using an ultrasonic Doppler flow detector. JP-1302 (0.03, 0.1, 0.3 and 1.0%) administered by the intranasal route decreased nasal cavity volumes from baseline values by 17, 25, 40 and 40%, respectively. Yohimbine (0.03, 0.1, 0.3 and 1.0%) decreased volumes by 19, 36, 46 and 53%, and topical administration of the nonselective alpha(1)-antagonist prazosin (0.001, 0.003, 0.01, 0.03 and 0.1%) decreased volumes by 6, 47, 56, 64 and 71%, respectively. JP-1302, yohimbine and prazosin, at the dose level tested, did not alter the blood pressure. The present set of experiments indicates that both alpha(1)- and alpha(2)-adrenergic receptors are involved in the maintenance of basal nasal patency in the cat. Moreover, alpha(2c)-receptors may play a significant role in the sympathetic control of upper airway function.


Geovariation in Fracture Risk among Patients Receiving Hemodialysis.
Fractures are a major source of morbidity and mortality in patients receiving dialysis. We sought to determine whether rates of fractures and tendon ruptures vary geographically. Data from the US Renal Data System were used to create four yearly cohorts, 2007-2010, including all eligible prevalent patients on hemodialysis in the United States on January 1 of each year. A secondary analysis comprising patients in a large dialysis organization conducted over the same period permitted inclusion of patient-level markers of mineral metabolism. Patients were grouped into 10 regions designated by the Centers for Medicare and Medicaid Services and divided by latitude into one of three bands: south, <35°; middle, 35° to <40°; and north, ≥40°. Poisson regression was used to calculate unadjusted and adjusted region-level rate ratios for events. Overall, 327,615 patients on hemodialysis were included. Mean (SD) age was 61.8 (15.0) years old, 52.7% were white, and 55.0% were men. During 716,962 person-years of follow-up, 44,014 fractures and tendon ruptures occurred, the latter being only 0.3% of overall events. Event rates ranged from 5.36 to 7.83 per 100 person-years, a 1.5-fold rate difference across regions. Unadjusted region-level rate ratios varied from 0.83 (95% confidence interval, 0.81 to 0.85) to 1.20 (95% confidence interval, 1.18 to 1.23), a 1.45-fold rate difference. After adjustment for a wide range of case mix variables, a 1.33-fold variation in rates remained. Rates were higher in north and middle bands than the south (north rate ratio, 1.18; 95% confidence interval, 1.13 to 1.23; middle rate ratio, 1.13; 95% confidence interval, 1.10 to 1.17). Latitude explained 11% of variation, independent of region. A complementary analysis of 87,013 patients from a large dialysis organization further adjusted for circulating mineral metabolic parameters and protein energy wasting yielded similar results. Rates of fractures vary geographically in the United States dialysis population, even after adjustment for known patient characteristics. Latitude seems to contribute to this phenomenon, but additional analyses exploring whether other factors might influence variation are warranted.


Experimental studies on bacterial product CANTASTIM derived from Pseudomonas aeruginosa with immunomodulatory properties. IV. Tyrosine phosphorylation as an effect of stimulation on different cell populations.
The bacterial product derived from Pseudomonas aeruginosa (trade mark-CANTASTIM) proved immunomodulatory effects in different systems, both in vitro and in vivo experimental animal models, as well as in clinical trials. Among the results obtained regarding CANTASTIM, the following immunomodulatory properties could be mentioned: an increase of the activated T cell subpopulations and humoral-mediated immune processes, facilitation of phagocytic processes, stimulation of cytotoxic activity reflected in the improvement of the capacity of defense in several tumoral and infectious diseases. To better elucidate the intimate mechanisms by which CANTASTIM modulates the cellular functions on different cellular populations, we used tyrosine phosphorylation as an estimate of cell activation on peripheral blood lymphocytes (PBL) and a monocyte cell line (THP-1). In PBL, the treatment with CANTASTIM renders them more susceptible to CD3 stimulation than non-treated cells. In monocytes, CANTASTIM and two phospholipid components of CANTASTIM modulated in a different manner the cellular adhesion on fibronectin and tyrosine phosphorylation leading to the conclusion that these phospholipid components do not fully explain CANTASTIM modulatory properties on cell adhesion processes.


Defective peroxisomal catabolism of branched fatty acyl coenzyme A in mice lacking the sterol carrier protein-2/sterol carrier protein-x gene function.
Gene targeting in mice was used to investigate the unknown function of Scp2, encoding sterol carrier protein-2 (SCP2; a peroxisomal lipid carrier) and sterol carrier protein-x (SCPx; a fusion protein between SCP2 and a peroxisomal thiolase). Complete deficiency of SCP2 and SCPx was associated with marked alterations in gene expression, peroxisome proliferation, hypolipidemia, impaired body weight control, and neuropathy. Along with these abnormalities, catabolism of methyl-branched fatty acyl CoAs was impaired. The defect became evident from up to 10-fold accumulation of the tetramethyl-branched fatty acid phytanic acid in Scp2(-/-) mice. Further characterization supported that the gene disruption led to inefficient import of phytanoyl-CoA into peroxisomes and to defective thiolytic cleavage of 3-ketopristanoyl-CoA. These results corresponded to high-affinity binding of phytanoyl-CoA to the recombinant rat SCP2 protein, as well as high 3-ketopristanoyl-CoA thiolase activity of the recombinant rat SCPx protein.


Conservative treatment of an anterior-lateral ankle dislocation without an associated fracture in a diabetic patient: a case report.
Anterior or anterior-lateral dislocation of the ankle is a rare condition that can be treated conservatively as well as any other similar types of ankle dislocations without associated fractures. We present a case report of an anterior-lateral ankle dislocation with a concomitant avulsion injury of the ankle's anterior capsule in a diabetic patient that was treated conservatively. At the patient's visit 12 months after the initial injury, he was asymptomatic with full range of motion of the ankle joint. To our knowledge, we could not identify this type of an injury in a diabetic patient that was treated successfully with conservative treatment in the existing literature.


[The symbol of the three kingdoms in nature and the pharmaceutical tokens of Paris].
A token from the Municipal Series in Paris (Paris, Bibliothèque Nationale, Cabinet des Médailles) discovered by C. Aurensan bears on the obverse the arms of Paris and on the reverse the symbol of the three kingdoms in nature with its legend. This reverse is identical to those tokens made for Parisian apothecaries in 1628, 1629 and 1632. Unfortunately the date which it bears is poorly engraved and one cannot determine whether it reads 1619 or 1629. Several arguments militate in favor of 1619.


Roles of protective factors and risk factors in suicidal ideation among adolescents in Taiwan.
To examine the role of protective factors and risk factors in suicidal ideation among adolescents in Taiwan based on a resilience protective model. A cross-sectional design was employed. A total of 390 adolescents aged 15-19 years were recruited from four high schools in Taiwan by stratified random sampling. An anonymous self-report questionnaire was used to collect demographic characteristics, suicidal ideation, depressive symptoms, life stress, emotion-focused coping, self-esteem, and problem-focused coping. Hierarchical multiple regression was used to test the hypotheses. Depressive symptoms were significantly and positively correlated with suicidal ideation. The interaction between depressive symptoms and self-esteem as well as between emotion-focused coping and problem-focused coping were significantly and negatively correlated with suicidal ideation. Depressive symptoms were a risk factor of suicidal ideation. Self-esteem can moderate the negative effect of depressive symptoms on suicidal ideation. Problem-focused coping can moderate the negative effects of emotion-focused coping on suicidal ideation. Public health nurses could cooperate with school nurses to periodically screen depressive symptoms and provide early interventions. Teaching parents and teachers methods for improving self-esteem of adolescents and enhancing adolescents to apply problem-focused coping strategies could be useful to reduce suicidal ideation of adolescents.


Duplex sonography of hepatic artery thrombosis after liver transplantation.
When hepatic artery thrombosis occurs after liver transplantation, another transplantation is required to ensure the patient's survival. Because of the importance of establishing this diagnosis, we reviewed the results of duplex sonography in 37 angiographically or surgically proved cases of hepatic artery thrombosis after liver transplantation. There were 20 children and 17 adults. Ten of the 20 children had angiographically documented hepatopetal arterial collaterals. Such collaterals were not seen in the adult patients. This subset of patients was evaluated separately to determine if intrahepatic arterial blood flow reestablished by collaterals after hepatic artery thrombosis was a cause of false-negative Doppler studies. Thirty-four (92%) of the 37 cases of hepatic artery thrombosis were correctly identified by Doppler. A Doppler pulse was not identified in any of the children with arterial collaterals. We conclude that duplex sonography is sensitive in detecting hepatic artery thrombosis after liver transplantation. Furthermore, the presence of blood flow in hepatopetal arterial collaterals does not cause false-negative examinations.


An imbalance of excitation and inhibition in the multisensory cortex impairs the temporal acuity of audiovisual processing and perception.
The neural integration of closely timed auditory and visual stimuli can offer several behavioral advantages; however, an overly broad window of temporal integration-a phenomenon observed in various neurodevelopmental disorders-could have far-reaching perceptual consequences. Non-invasive studies in humans have suggested that the level of GABAergic inhibition in the multisensory cortex influences the temporal window over which auditory and visual stimuli are bound into a unified percept. Although this suggestion aligns with the theory that an imbalance of cortical excitation and inhibition alters multisensory processing, no prior studies have performed experimental manipulations to determine the causal effects of a reduction of GABAergic inhibition on audiovisual temporal perception. To that end, we used a combination of in vivo electrophysiology, neuropharmacology, and translational behavioral testing in rats to provide the first mechanistic evidence that a reduction of GABAergic inhibition in the audiovisual cortex is sufficient to disrupt unisensory and multisensory processing across the cortical layers, and ultimately impair the temporal acuity of audiovisual perception and its rapid adaptation to recent sensory experience. Looking forward, our findings provide support for using rat models to further investigate the neural mechanisms underlying the audiovisual perceptual alterations observed in neurodevelopmental disorders, such as autism, schizophrenia, and dyslexia.


Spatially regularized machine learning for task and resting-state fMRI.
Reliable mapping of brain function across sessions and/or subjects in task- and resting-state has been a critical challenge for quantitative fMRI studies although it has been intensively addressed in the past decades. A spatially regularized support vector machine (SVM) technique was developed for the reliable brain mapping in task- and resting-state. Unlike most existing SVM-based brain mapping techniques, which implement supervised classifications of specific brain functional states or disorders, the proposed method performs a semi-supervised classification for the general brain function mapping where spatial correlation of fMRI is integrated into the SVM learning. The method can adapt to intra- and inter-subject variations induced by fMRI nonstationarity, and identify a true boundary between active and inactive voxels, or between functionally connected and unconnected voxels in a feature space. The method was evaluated using synthetic and experimental data at the individual and group level. Multiple features were evaluated in terms of their contributions to the spatially regularized SVM learning. Reliable mapping results in both task- and resting-state were obtained from individual subjects and at the group level. A comparison study was performed with independent component analysis, general linear model, and correlation analysis methods. Experimental results indicate that the proposed method can provide a better or comparable mapping performance at the individual and group level. The proposed method can provide accurate and reliable mapping of brain function in task- and resting-state, and is applicable to a variety of quantitative fMRI studies.


Digital radiography of interproximal caries: effect of different filters.
The aim of this study was to compare the effect of different image processing modes (filters) on reproducibility and validity of the assessment of interproximal carious lesions on digitized radiographic images. Standardized radiographs of 34 extracted teeth exhibiting interproximal caries were obtained. All radiographs were digitized and using the FRIACOM-software the central depth (CD) of each carious lesion was measured on the unchanged radiographic image and after use of five different filters with 7fold and 18fold magnification. All measurements were repeated after 1 week to estimate reproducibility. Histometric CD assessments provided a gold standard for comparison with the radiographic measurements (validity). Neither reproducibility nor validity of CD measurements were improved by one of the filters. Measurements of dentinal lesions showed a statistically higher variability than those of enamel lesions (p<0.001). 18fold magnification provided more valid CD measurements than 7fold magnification (p<0.001). In this study digital manipulations of radiographic images failed to result in statistically significantly improved reproducibility or validity of CD measurements.


"I couldn't have seen it coming": the impact of negative self-relevant outcomes on retrospections about foreseeability.
We examined a phenomenon related to hindsight bias, specifically, retrospective judgements about the foreseeability of an outcome. We predicted that negative, self-relevant outcomes would be judged as less foreseeable by the recipient of the outcome than by others, unlike either positive outcomes or outcomes that are not self-relevant. In the context of a "stock market decision-making game", the hypothetical stock selected by one of two players showed an extreme increase or decrease. As predicted, the player who received an extreme negative outcome reported that this outcome was less foreseeable than did the opponent and an observer, for whom the outcome was less self-relevant. For no other kind of outcome was there a difference between the recipient of an outcome, the opponent, and the observer. The findings have several implications, including the possibility that hindsight bias should be considered as a special case of retrospective foreseeability.


Ethnic comparisons in diabetes and insulin levels.
The prevalence of non insulin dependent diabetes mellitus (NIDDM) is increasing exponentially. While the genetic causes of NIDDM remain unclear, the differences in prevalence of NIDDM over time, between and within different ethnic groups highlight the importance of environmental factors in the development of NIDDM in any given individual. Besides the classical risk factors for NIDDM such as obesity and indolence, the role of intra-uterine over-exposure or deficit of nutrients is increasingly felt to be of importance in the aetiology of NIDDM. Indeed, ethnic differences in hyperinsulinaemia, can be detected at birth in some populations. In utero exposure to increased fuel supply may be of particular importance in Polynesian and American Indian populations. If this is so, efforts to control NIDDM will take several generations to be successful.


Invasive fungal infections in patients with COVID-19: a review on pathogenesis, epidemiology, clinical features, treatment, and outcomes.
COVID-19 is frequently associated with the onset of secondary infections, especially in severe cases treated in the intensive care unit. While bacterial pathogens are the most frequently encountered causative agents, several factors put SARS-CoV-2 infected patients at a heightened risk of invasive fungal infections, which have been recognized as a substantial cause of morbidity and mortality in this population. Moreover, the frequent occurrence of these complications in severely ill subjects and the absence of pathognomonic features, together with the emergence of fungal species with reduced susceptibility to first-line treatments and the difficult to manage safety profile of several antifungal drugs, demand an additional focus on these rare but challenging complications. In this review, we will summarize the currently available literature on fungal superinfections in COVID-19 patients, exploring the pathogenesis, epidemiology, clinical features, treatment, and outcomes.


[Analysis of GHB and Its Precursors in Urine and Their Forensic Application].
To establish the method to analyze γ-hydroxybutyric acid (GHB) and its precursors 1,4-butanediol (1,4-BD) and gamma-butyrolactone (GBL) in urine through LC-MS/MS and provide evidence for related cases. GHB-d6 and MOR-d3 were used as the internal standard. The urine sample was separated by LC after protein precipitation with methanol. The electrospray ion source was for ionization. Each compound was detected through multiple-reaction monitoring (MRM) mode. The limits of detection of GHB and its precursors 1,4-BD and GBL were 0.1, 0.1 and 2 μg/mL. The accuracy was 87.6%-98.1%. The intra-day and inter-day precisions were less than 15% and matrix effects were higher than 80%. The method is high sensitive, simple, rapid, specific and with high reliability. This study has provided technical support and basic data for forensic cases involving GHB.


Hepatitis in refugees who settle in Australia.
The World Health Organisation estimates that 2 billion people have been infected with hepatitis B and about 180 million people infected with hepatitis C worldwide. More than 350 million have chronic hepatitis B and 130 million have chronic hepatitis C infection. Most infections of hepatitis B and C are from unsafe injection practices, both medical and nonmedical; from household contacts; or, in the case of hepatitis B, from 'vertical' transmission from mother to child. This article discusses screening and management of hepatitis B and C in refugees who settle in Australia. Most people carrying hepatitis will be asymptomatic with infection detected by screening. Refugees need counselling, education and support to come to terms with the implications of hepatitis B and C for both themselves and their families. In Australia both viruses can be treated in those with active infection and general practitioners can be involved in diagnosis, follow up and shared care management.


Rotational Stability After Implantation of Two Different Phakic Toric Intraocular Lenses.
To compare clinical outcomes and rotational stability of the toric implantable Collamer lens (TICL) and toric implantable phakic contact lens (TIPCL). Charts were reviewed from January 2011 to January 2023 to identify all TICLs and TIPCLs implanted by a single surgeon. Implant size was generally chosen according to the manufacturer's recommendation, but 15 TIPCLs 0.25 mm larger than recommended to increase vaulting were included. Eighty-four TICLs and 98 TIPCLs were identified and yielded excellent refractive and visual results in eyes with high myopic astigmatism at the last follow-up visit. No case of acute glaucoma or cataract induction was observed. In total, 15 (8.2%) rotated lenses were recorded; 2 (2.4%) TICLs and 13 (13.3%) TIPCLs (P = .013). Eyes in both groups were similar in preoperative spherical equivalent, cylinder, white-to-white distance, anterior chamber depth (ACD), anterior chamber angle, and mean follow-up times (P = .925, .673, .822, .794, .358, and .873, respectively). Average TICL size was larger than TIPCL size (P < .001). Rotation of the lenses was positively correlated with cylinder and negatively correlated with ACD but not with vaulting (P = .001, r = 0.253; P = .011, r = -0.193; P = .488, r = -0.057; respectively). Vaulting was positively correlated with preoperative ACD (P ≤ .001, r = .329). In eyes with a rotated TIPCL, preoperative cylinder was higher and ACD was shallower than in eyes with a stable TIPCL (P = .001 and .007, respectively). Increasing the implant size had no significant effect on rotation rate (P = .685). Although both implants were safe and effective in highly myopic eyes, TICL rotated less frequently than TIPCL and required fewer secondary interventions. Rotation was correlated with preoperative cylinder and ACD but not lens vaulting. [J Refract Surg. 2023;39(7):463-472.].


Tufted apple bud moth (Lepidoptera: Tortricidae) management model for processing apples based on early season pheromone trap capture.
Sixteen years of archived tufted apple bud moth, Platynota idaeusalis (Walker), trap capture data were compared with archived fruit injury data collected at the Penn State University Fruit Research and Extension Center to define the relationship of trap capture to fruit injury. Pheromone trap capture until 15 June was the best predictor of fruit injury at harvest. Using the regression equation of fruit injury on early season trap capture, and other assumptions about insecticide cost and fruit yield, a management model was developed for apple growers in the Mid-Atlantic region. When the model was tested on archived trap capture and fruit injury data, the results indicated that a grower would lose money on average by always treating and save money on average by never treating. By using the model, a grower could expect to save more money than by never treating. The model showed sensitivity to fruit price, insecticide price, and fruit yield.


The influence of spatial configuration on the frequency of use of hand sanitizing stations in health care environments.
The lack of user-friendly, accessible, and visible hand sanitizing stations (HSSs) in health care environments are significant factors affecting low hand hygiene compliance rates among caregivers. To determine whether the simulated parameters of visibility and global traffic flow score for an HSS can influence the frequency of use of that HSS. Space syntax was used to measure virtual simulation of spatial layouts of 3 units to provide quantitative visibility and global traffic flow scores for each HSS. The frequency of use of HSSs was measured for 2 weeks in 3 units in a community hospital through electronic tracking with self-developed motion sensors. Behavioral observations were also conducted during the same period to validate hand hygiene data obtained through electronic tracking. Linear models were used to tests how much variance in use is accounted for when visibility and/or global traffic flow are included in the model. When the visibility score for an HSS increases (decrease), frequency of use of the HSS will increase (decrease) (F [5, 65] = 13.877; P < .001). When the global traffic flow score for an HSS increases (decrease), frequency of use of the HSS will increase (decrease) (F [5, 65] = 13.877; P < .001). This study proposed and validated a novel approach of using space syntax simulations to predict and optimize hand hygiene behavior.


Calcergy inhibited by calciphylactic challengers.
The subcutaneous calcification effected in the rat at sites directly treated with calcergens, such as lead acetate, CeCl(3), CaCl(2), and KMnO(4), is inhibited by simultaneous local application of various calciphylactic challengers, but not by many other compounds.


Grasping with a soft glove: intrinsic impedance control in pneumatic actuators.
The interaction of a robotic manipulator with unknown soft objects represents a significant challenge for traditional robotic platforms because of the difficulty in controlling the grasping force between a soft object and a stiff manipulator. Soft robotic actuators inspired by elephant trunks, octopus limbs and muscular hydrostats are suggestive of ways to overcome this fundamental difficulty. In particular, the large intrinsic compliance of soft manipulators such as 'pneu-nets'-pneumatically actuated elastomeric structures-makes them ideal for applications that require interactions with an uncertain mechanical and geometrical environment. Using a simple theoretical model, we show how the geometric and material nonlinearities inherent in the passive mechanical response of such devices can be used to grasp soft objects using force control, and stiff objects using position control, without any need for active sensing or feedback control. Our study is suggestive of a general principle for designing actuators with autonomous intrinsic impedance control.


Is clinician-supported use of a mindfulness smartphone app a feasible treatment for depression? A mixed-methods feasibility study.
Depression is the leading cause of disability globally and has serious consequences for the individual, their family and for society. Effective, accessible and affordable treatments are urgently needed. In-person group-based mindfulness-based interventions are an effective treatment for depression, but are not widely available and can be costly. Clinician supported use of mindfulness self-help resources such as mindfulness smartphone applications could widen access at a reduced cost, but there are key feasibility questions that need answering. This is a mixed-methods feasibility study of a blended intervention involving the mindfulness smartphone app Headspace alongside six clinician support sessions with mental health treatment seeking adults experiencing moderate to moderately severe symptoms of depression. In line with recommendations for feasibility studies, we examine whether: (1) it is possible to recruit participants to this novel intervention, (2) participants engage with the intervention, (3) participants and clinicians find the intervention acceptable, and (4) pre-post outcomes on measures of depression (primary outcome), anxiety, wellbeing, mindfulness, self-compassion, rumination and worry indicate effectiveness. Findings show that recruitment is feasible with 54 participants enrolled in the intervention within a 6-month window. In terms of engagement, 44.4% completed at least 80% of recommended Headspace sessions and 72.2% of participants attended at least three clinician support sessions. Clinician-supported Headspace was deemed acceptable by participants and clinicians. Pre-post effect sizes were statistically significant and in the small-medium or medium-large range on all outcomes, with an effect size of d = 0.69 (95% CI: 0.34-1.04) for the primary outcome of depression symptom severity. The number of Headspace sessions engaged with was associated with greater reduction in depression symptom severity. Findings suggest that a blended intervention combining Headspace with clinician support has potential as a first-line treatment for moderate/moderately severe depression, but findings are too preliminary to recommend the intervention outside of a research trial. Important caveats are noted including the need for future research to examine predictors of engagement with Headspace sessions so that engagement can be enhanced, to measure the longer term effects of such interventions and to better understand the potential for lasting negative effects of the intervention so that these can be minimised.


Decidual Vasculopathy: Placental Location and Association With Ischemic Lesions.
Decidual vasculopathy (DV) is a general term for a number of lesions involving uteroplacental vessels. It is often seen in preeclamptic placentas and indicates a disorder of uteroplacental malperfusion and is associated with placental ischemia and infarction. Although some have advocated submitting special sections in order to better document DV, it is unclear which placental sections have the highest yield in demonstrating these abnormal vessels. Seventy-six consecutive cases of decidual vasculopathy were identified and evaluated for location of DV, as well as presence of other lesions of ischemic change, infarcts, and retroplacental hematomas. Sections reviewed were the membrane roll (MR), full thickness (FT) sections of the placental disc, and sections specifically of the basal plate (BP). DV was found in the MR in 67.1% of cases, in FT sections in 32.9%, and in the BP in 25.0% of cases ( P value = .004). DV was exclusive to the MR in 53.9%, the FT in 14.5%, and the BP in 9.2%. DV was present in 2 locations in 19.7% and in all 3 locations in 2.6%. The presence of DV in any location (MR, FT, and BP) was associated with placental ischemic change but not specifically with infarcts or retroplacental hematomas. The specific location of DV showed no difference in the presence of placental lesions. Our findings indicate DV is often present in 1 location and is associated with lesions of malperfusion. It is recommended that when clinically indicated, additional sections are submitted to demonstrate decidual vasculopathy.


Xenon Tetrafluoride: Reaction with Aqueous Solutions.
Xenon tetrafluoride reacts with water to yield xenon, oxygen, hydrofluoric acid, and a very soluble species containing xenon. Evaporation of the solution yields a white, crystal-line substance which has been identified as xenon (VI) oxide, XeO(3).


Pesticide residue transfer in Thai farmer families: using structural equation modeling to determine exposure pathways.
Use of pesticides in agriculture may lead to downstream exposure of farmers' families to pesticide residues inadvertently taken home. Identification of the independent contribution of different exposure pathways from the farmer to their children can provide clear targets to reduce exposure of farmers' children. Individual contributions of different pesticide transfer exposure pathways were investigated using structural equation modeling methods, and the benefits of these methods compared to standard multiple regression are described. A total of 72 Thai families, consisting of a farmer, a spouse, and a child, participated in this study. Family members completed a questionnaire and self-collected three spot morning urine samples in the spraying season. Urine samples were analyzed for diethyl phosphate, diethyl thiophosphate, diethyl dithiophosphate, dimethyl phosphate, dimethyl thiophosphate, and dimethyl dithiophosphate. A path model was developed based on an a priori hypothesized framework to examine the individual contributions of different exposure pathways that may directly or indirectly affect transfer of pesticide residues from farmers to their children. Transfer from the farmer to the child occurs indirectly, primarily through transfer to the spouse in the first instance, but also through contamination of the home environment. Clear targets for interventions are directly the reduction of farmers' take-home exposures and indirectly frequent cleaning of the home to avoid buildup of pesticide residues.


Characterization of a SPECT pinhole collimator for optimal detector usage (the lofthole).
In single-photon emission computed tomography (SPECT), multi-pinhole collimation is often employed nowadays. Most multi-pinhole collimators avoid overlap (multiplexing) of the projections on the detector. This can be done by using additional shielding or by spacing the pinholes far enough apart. Using additional shielding has the drawback that it increases weight, design complexity and cost. Spacing the pinholes far enough apart results in sub-optimal detector usage, the valuable detector area is not entirely used. This is due to the circular projections of pinholes on the detector; these ellipses can not be tiled with high detector coverage. To overcome this we designed a new pinhole geometry, the lofthole, that has a rectangular projection on the detector. The lofthole has a circular aperture and a rectangular entrance/exit opening. Sensitivity formulae have been derived for pinholes and loftholes. These formulae take the penumbra effect into account; the proposed formulae do not take penetration into account. The derived formulae are valid for geometries where the field-of-view and the sensitivity of the aperture are solely limited by the exit window. A flood map measurement was performed to compare the rectangular projection of a lofthole with the circular projection of a pinhole. Finally, measurements were done to compare the amount of penetration of pinholes with the amount of penetration of a lofthole. A square lofthole collimator has less penetration than a knife-edge pinhole collimator that irradiates the same rectangular detector area with full coverage. A multi-lofthole collimator allows high detector coverage without using additional shielding. An additional advantage is the lower amount of penetration.


Dual tasking negatively impacts obstacle avoidance abilities in post-stroke individuals with visuospatial neglect: Task complexity matters!
Persons with perceptual-attentional deficits due to visuospatial neglect (VSN) after a stroke are at a risk of collisions while walking in the presence of moving obstacles. The attentional burden of performing a dual-task may further compromise their obstacle avoidance performance, putting them at a greater risk of collisions. The objective of this study was to compare the ability of persons with (VSN+) and without VSN (VSN-) to dual task while negotiating moving obstacles. Twenty-six stroke survivors (13 VSN+, 13 VSN-) were assessed on their ability to (a) negotiate moving obstacles while walking (locomotor single task); (b) perform a pitch-discrimination task (cognitive single task) and (c) simultaneously perform the walking and cognitive tasks (dual task). We compared the groups on locomotor (collision rates, minimum distance from obstacle and onset of strategies) and cognitive (error rates) outcomes. For both single and dual task walking, VSN+ individuals showed higher collision rates compared to VSN- individuals. Dual tasking caused deterioration of locomotor (more collisions, delayed onset and smaller minimum distances) and cognitive performances (higher error rate) in VSN+ individuals. Contrastingly, VSN- individuals maintained collision rates, increased minimum distance, but showed more cognitive errors, prioritizing their locomotor performance. Individuals with VSN demonstrate cognitive-locomotor interference under dual task conditions, which could severely compromise safety when ambulating in community environments and may explain the poor recovery of independent community ambulation in these individuals.


Leprosy incidence: six years follow-up of a population cohort in Bangladesh.
With approximately 250,000 new leprosy cases detected annually, transmission of M. leprae appears to be ongoing in many areas of the world. By studying prospectively the number of leprosy patients found in a population sample at the beginning of the study (prevalence) and the number of new patients found during the 6-year observation period (incidence), we aim to understand better the transmission of M. leprae and the burden of disease. To establish the prevalence and incidence rates of leprosy in the general population of a high endemic area in Bangladesh, we followed prospectively 20,218 individuals from a random cluster sample of the population and examined them at 2-yearly intervals for 6 years. At intake we found 27 new leprosy cases, indicating a prevalence of previously undiagnosed leprosy of 13.3/10,000. Follow-up at 2, 4 and 6 years revealed 17, 16, and eight new cases, respectively, representing incidence rates of 4.0, 4.5 and 2.3/10,000 PYAR, respectively. The incidence rate over 6 years was 3.7/10,000 PYAR. The observed incidence rate is three times higher than the new case detection rate in the same area. Of all 68 new leprosy cases, five (7%) had MB leprosy. The proportion of children under 15 years was 24%. The proportion of female patients was 60%, but the incidence rate of leprosy was the same for males and females. The decline in incidence of leprosy in a general population sample is less pronounced than routine data from a control programme led us to expect.


[Immunometric tests system for glycoprotein hormones and their free subunits].
Highly specific sensitive immunoenzymometric assays were established for human glycoprotein hormones, the common free alpha-subunit of glycoprotein hormones and the free beta-subunit of human chorionic gonadotropin, using a large panel of monoclonal antibodies previously produced in our laboratory. The significance of serum levels of human chorionic gonadotropin and its free subunits under physiological conditions, as well as their prognostic value in human chorionic gonadotropin-producing tumours was determined in vitro and in vivo. These investigations revealed that all three analytes were present in the sera of the majority of normal individuals; moreover, the percentage of positive sera for these tumour markers in patients suffering from seminomatous and non-seminomatous testicular cancers was significantly elevated when two, or even better, all three parameters were determined.


Spontaneous rupture of the extensor pollicis longus tendon after conservative treatment of a non-displaced distal radius fracture in an adolescent.
A spontaneous rupture of the extensor pollicis longus (EPL) tendon after a fracture of the distal radius is a known complication in adults. In contrast, there are a paucity of reports concerning EPL tendon ruptures in children and adolescents. The authors present a case of a spontaneous rupture of the EPL tendon in a 15-year-old girl after a non-displaced distal radius fracture. The patient had no predisposing factors including rheumatoid arthritis or steroid injection. During surgery, the EPL tendon was found to be ruptured at the extensor retinaculum (third compartment). Extensor indicis proprius (EIP) to EPL transfer was performed. At the 18-month follow-up, the patient was asymptomatic and showed satisfactory thumb function, with normal active extension.


Isolation and Characterization of Poeciguamerin, a Peptide with Dual Analgesic and Anti-Thrombotic Activity from the Poecilobdella manillensis Leech.
When Poecilobdella manillensis attacks its prey, the prey bleeds profusely but feels little pain. We and other research teams have identified several anticoagulant molecules in the saliva of P. manillensis, but the substance that produces the paralyzing effect in P. manillensis is not known. In this study, we successfully isolated, purified, and identified a serine protease inhibitor containing an antistasin-like domain from the salivary secretions of P. manillensis. This peptide (named poeciguamerin) significantly inhibited elastase activity and slightly inhibited FXIIa and kallikrein activity, but had no effect on FXa, trypsin, or thrombin activity. Furthermore, poeciguamerin exhibited analgesic activity in the foot-licking and tail-withdrawal mouse models and anticoagulant activity in the FeCl3-induced carotid artery thrombosis mouse model. In this study, poeciguamerin was found to be a promising elastase inhibitor with potent analgesic and antithrombotic activity for the inhibition of pain and thrombosis after surgery or in inflammatory conditions.


Enterocyte response to ischemia is dependent on differentiation state.
Enterocytes at the tips of microvilli are more sensitive to an ischemic insult than those cells residing in the crypts, an effect thought to be due to a relative lack of collateral flow. We speculated that this increased cellular sensitivity to ischemia might be an intrinsic feature of the cells related to their differentiated phenotype. To test this hypothesis, enterocyte response to ischemia was determined using both in vivo and in vitro models. For the in vivo studies, male Sprague-Dawley rats underwent laparotomy, and small intestinal ischemia was induced by clamping the superior mesenteric artery for 30 or 60 minutes, after which reperfusion was allowed for various time points up to 4 days. Injury was assessed histologically, as well as with Northern blots, probing for the enterocyte differentiation markers intestinal alkaline phosphatase and lactase, as well as the gut-epithelial marker villin. Mucosal changes consistent with ischemia/reperfusion injury were evident--that is, a rapid inflammatory response followed by progressive villus cell loss beginning at the tips and progressing to the crypts, depending on the degree of insult, with an eventual return to normal microanatomy. Intestinal alkaline phosphatase and lactase were lost immediately after ischemia and returned with reperfusion, confirming that the differentiated cells are particularly sensitive to ischemic injury. The in vitro studies employed two separate models of enterocyte differentiation: sodium butyrate-treated HT-29 cells and Caco-2 cells maintained for 7 days after confluence. In both models, undifferentiated and differentiated cells were subjected to treatment with 2-deoxyglucose and oligomycin-A (in vitro model of ischemia) and apoptosis was assessed by fluorescence-activated cell sorting analysis. Differentiation of both cell lines resulted in a significantly greater apoptotic response to ischemia compared to undifferentiated cells exposed to an identical insult. We conclude that differentiated enterocytes may be inherently more sensitive to ischemia-induced injury than their undifferentiated counterparts. These findings call into question the popularly held belief that villus tip cells are more susceptible to ischemia because of their location relative to the microvascular anatomy.


Effect of HMGN2 on proliferation and apoptosis of MCF-7 breast cancer cells.
We investigated the effect of high mobility group protein N2 (HMGN2) on the proliferation and apoptosis of the human MCF-7 breast cancer cell line, and its effect on tumor growth in a subcutaneous heterotopic transplantation tumor model of breast cancer. The cell viability assay was used to verify the effect of the recombinant human HMGN2 on MCF-7 cell proliferation. The Transwell chamber assay was used to verify the effect of HMGN2 on MCF-7 cell migration. Flow cytometry and Hoechst staining were used to detect the effect of HMGN2 on MCF-7 cell apoptosis. MCF-7 was injected to establish a subcutaneous heterotopic transplantation tumor model of breast cancer in nude mice. The size, weight and volume of tumor in each group were compared after the administration of different concentrations of HMGN2 solution around the tumor tissue at day 1, 3, 5 and 7. The tumor tissue was removed and cut into sections, and the apoptotic cells in tumors of nude mice were detected by a TUNEL kit. The CCK-8 assay showed that HMGN2 at different concentrations inhibited the proliferation of the MCF-7 breast cancer cells, and the proliferation of MCF-7 cells were significantly inhibited when the concentration of HMGN2 reached 3 µg/ml (P<0.01). The Transwell chamber assay showed that 3 µg/ml of HMGN2 significantly decreased the migration capacity of MCF-7 cells (P<0.01). Flow cytometry and Hoechst staining showed that 3 µg/ml of HMGN2 significantly increased apoptosis of MCF-7 cells (P<0.01). After the nude mouse model of breast cancer was established, HMGN2 at different concentrations was injected around the tumor tissue at day 1, 3, 5 and 7. We demonstrated that the growth of breast cancer was significantly inhibited when the concentration of HMGN2 reached 15 µg/ml. TUNEL staining showed that the number of apoptotic cells in the 15 µg/ml dose group was significantly higher than that in the control group (P<0.01). Therefore, in vitro and in vivo experiments proved that recombinant human HMGN2 could significantly inhibit the proliferation and migration of breast cancer cells, which increased the apoptosis of breast cancer cells and exerted anti-breast cancer effects, which enriched our understanding of the biological roles of HMGN2.


Titration ELISA as a Method to Determine the Dissociation Constant of Receptor Ligand Interaction.
The dissociation constant describes the interaction between two partners in the binding equilibrium and is a measure of their affinity. It is a crucial parameter to compare different ligands, e.g., competitive inhibitors, protein isoforms and mutants, for their binding strength to a binding partner. Dissociation constants are determined by plotting concentrations of bound versus free ligand as binding curves. In contrast, titration curves, in which a signal that is proportional to the concentration of bound ligand is plotted against the total concentration of added ligand, are much easier to record. The signal can be detected spectroscopically and by enzyme-linked immunosorbent assay (ELISA). This is exemplified in a protocol for a titration ELISA that measures the binding of the snake venom-derived rhodocetin to its immobilized target domain of α2β1 integrin. Titration ELISAs are versatile and widely used. Any pair of interacting proteins can be used as immobilized receptor and soluble ligand, provided that both proteins are pure, and their concentrations are known. The difficulty so far has been to determine the dissociation constant from a titration curve. In this study, a mathematical function underlying titration curves is introduced. Without any error-prone graphical estimation of a saturation yield, this algorithm allows processing of the raw data (signal intensities at different concentrations of added ligand) directly by mathematical evaluation via non-linear regression. Thus, several titration curves can be recorded simultaneously and transformed into a set of characteristic parameters, among them the dissociation constant and the concentration of binding-active receptor, and they can be evaluated statistically. When combined with this algorithm, titration ELISAs gain the advantage of directly presenting the dissociation constant. Therefore, they may be used more efficiently in the future.


Characteristics of Transmitted Drug-Resistant HIV-1 in Recently Infected Treatment-Naive Patients in Japan.
Progress in antiretroviral treatment has led to fewer virological failure cases, but 10%-20% of treatment-naive HIV/AIDS cases are reported to harbor drug-resistant strains, suggesting transmission of drug-resistant HIV. We aimed to determine the trend in prevalence of transmitted drug-resistant (TDR) HIV in Japan, particularly in recently infected patients. Drug-resistance test was performed on 3904 HIV-1-infected cases newly diagnosed between 2007 and 2012. The number of cases infected within 6 months [recent seroconverters (RS)] was estimated by BED assay of 2700 plasma samples. Characteristics of RS cases were further analyzed. The overall prevalence of TDR was 9.1%, ranging from 7.3% in 2008% to 12.5% in 2010. Among 1403 subtype B/E/D cases with >50 CD4 T cell counts and >1000 HIV copies per milliliter, 468 (33.4%) were estimated to be RS. The prevalence of RS was significantly higher among cases who were male, Japanese, and men who have sex with men. The prevalence of TDR did not differ significantly between recent and long-term seroconverters (8.5% vs. 9.2%, respectively, P = 0.68). Common mutations in both groups were M46I/L and T215 revertants. Furthermore, sequences with these mutations, K103N and D30N/N88D formed clusters on phylogenetic trees. Our study clarified an increase in prevalence of TDR in Japan from 2007 to 2012. The phylogenetic clustering of cases with M46I/L or T215 revertants suggests that HIV with these mutations have become circulating strains. Furthermore, detailed analyses showed that Japanese men who have sex with men are more aware of their risk of HIV infection.


Update on nephrolithiasis management.
Urolithiasis affects 10%-15% of the population in their lifetime. After spontaneous passage or surgical treatment, a subset of these patients will have recurrent calculi. These recurrent stone events are significantly morbid and can potentially lead to serious chronic renal disease, thus prevention is a very important treatment goal. Fortunately, a reversible metabolic abnormality can be identified in over 90% of recurrent stone formers. Thus, a detailed metabolic evaluation using 24 hour urine collections and serum tests is indicated in patients at high risk for stone recurrence. Once the patient's underlying urinary physicochemical and physiologic derangements are defined, targeted medical therapy can be initiated in order to prevent growth of pre-existing stones and recurrent stone formation. In this paper, we provide a review of the currently available selective and nonselective pharmacologic treatments for urolithiasis. Furthermore, we discuss a number of investigational agents for kidney stone prevention. Although many of these agents are effective, there remain numerous clinical scenarios where currently available therapies are inadequate.


Inter-rater and intrarater reliability of the South African Triage Scale in low-resource settings of Haiti and Afghanistan.
The South African Triage Scale (SATS) has demonstrated good validity in the EDs of Médecins Sans Frontières (MSF)-supported sites in Afghanistan and Haiti; however, corresponding reliability in these settings has not yet been reported on. This study set out to assess the inter-rater and intrarater reliability of the SATS in four MSF-supported EDs in Afghanistan and Haiti (two trauma-only EDs and two mixed (including both medical and trauma cases) EDs). Under classroom conditions between December 2013 and February 2014, ED nurses at each site assigned triage ratings to a set of context-specific vignettes (written case reports of ED patients). Inter-rater reliability was assessed by comparing triage ratings among nurses; intrarater reliability was assessed by asking the nurses to retriage 10 random vignettes from the original set and comparing these duplicate ratings. Inter-rater reliability was calculated using the unweighted kappa, linearly weighted kappa and quadratically weighted kappa (QWK) statistics, and the intraclass correlation coefficient (ICC). Intrarater reliability was calculated according to the percentage of exact agreement and the percentage of agreement allowing for one level of discrepancy in triage ratings. The correlation between years of nursing experience and reliability of the SATS was assessed based on comparison of ICCs and the respective 95% CIs. A total of 67 nurses agreed to participate in the study: In Afghanistan there were 19 nurses from Kunduz Trauma Centre and nine from Ahmed Shah Baba; in Haiti, there were 20 nurses from Martissant Emergency Centre and 19 from Tabarre Surgical and Trauma Centre. Inter-rater agreement was moderate across all sites (ICC range: 0.50-0.60; QWK range: 0.50-0.59) apart from the trauma ED in Haiti where it was moderate to substantial (ICC: 0.58; QWK: 0.61). Intrarater agreement was similar across the four sites (68%-74% exact agreement); when allowing for a one-level discrepancy in triage ratings, intrarater reliability was near perfect across all sites (96%-99%). No significant correlation was found between years of nursing experience and reliability. The SATS has moderate reliability in different EDs in Afghanistan and Haiti. These findings, together with concurrent findings showing that the SATS has good validity in the same settings, provide evidence to suggest that SATS is suitable in trauma-only and mixed EDs in low-resource settings.


High-level expression of porcine liver cytochrome P-450 reductase catalytic domain in Escherichia coli by modulating the predicted local secondary structure of mRNA.
A direct expression system for the solubilized catalytic domains of NADPH-cytochrome P-450 reductase (sCPR) from rat (RsCPR) and porcine (PsCPR) in Escherichia coli cells was constructed using the expression plasmid pCWori(+). PsCPR was minimally expressed, whereas RsCPR was highly expressed. Replacement of the nucleotides encoding Thr(60)Ser(61)Ser(62) in PsCPR with those for Ala(60)Pro(61)Pro(62) in RsCPR markedly increased the expression level of the protein. The local secondary structures of the mRNAs, which were predicted with the prediction program GeneBee (http://www.genebee.msu.su), suggested that the intramolecular double strand between the ribosome binding site (RBS) and the Thr(60)Ser(61)Ser(62) codons in PsCPR, and/or the base-pairing at the initiation codon of the mRNAs significantly affected protein expression. Silent mutations were systematically introduced into the codons for Thr(58) and Thr(60)Ser(61) in PsCPR to modulate the local secondary structure of the mRNA. The expression level of the silently mutated PsCPR suggests that the expression level of PsCPR depends on the stability of the local structure at the RBS in the mRNA. A high-level expression system for wild-type PsCPR was constructed by introducing silent mutations at the codons for Thr(60)Ser(61) in PsCPR. The purified PsCPR showed the characteristic absorption spectral changes of sCPR after reduction with NADPH. The yield of purified PsCPR from 1 liter of culture fluid was 45.8 mg. These results substantiate that the introduction of silent mutations in the section of the gene encoding the N-terminal region of the protein based on the predicted local secondary structure of the mRNA at the RBS is a useful approach to control and increase the expression level of heterologous proteins in E. coli cells.


Effect of different periods of preconditioning with saliva on Candida albicans adhesion to a denture base resin by crystal violet staining and XTT assay.
The role of saliva on Candida adhesion to biomaterials has not been clearly defined. The present study investigates whether different periods of preconditioning with saliva would influence the adhesion of Candida albicans to a denture base resin. Ninety samples of acrylic resin with smooth surfaces were made and then divided into five groups: one control without saliva, and four experimental groups conditioned in saliva for periods of 30 min, 1, 3, or 12 h. Candida adhesion was evaluated by crystal violet staining and 2,3-bis(2-methoxy-4-nitro-5-sulfophenyl)-5-([phenylamino] carbonyl)-2H-tetrazolium-hydroxide assay. The one-way analysis of variance revealed that there were no significant differences among the mean number of adherent cells or among the mean absorbance for all groups. No significant correlation was found between the two methods used for assessing Candida albicans adhesion. The different periods of preconditioning with saliva had no significant influence on the adhesion of Candida albicans to the denture base acrylic resin.


Wide-angle ITER-prototype tangential infrared and visible viewing system for DIII-D.
An imaging system with a wide-angle tangential view of the full poloidal cross-section of the tokamak in simultaneous infrared and visible light has been installed on DIII-D. The optical train includes three polished stainless steel mirrors in vacuum, which view the tokamak through an aperture in the first mirror, similar to the design concept proposed for ITER. A dichroic beam splitter outside the vacuum separates visible and infrared (IR) light. Spatial calibration is accomplished by warping a CAD-rendered image to align with landmarks in a data image. The IR camera provides scrape-off layer heat flux profile deposition features in diverted and inner-wall-limited plasmas, such as heat flux reduction in pumped radiative divertor shots. Demonstration of the system to date includes observation of fast-ion losses to the outer wall during neutral beam injection, and shows reduced peak wall heat loading with disruption mitigation by injection of a massive gas puff.


Hypotonic contrast media is more toxic than isotonic contrast media on endothelial cells in vivo and in vitro.
The aim of the current study was to investigate the cytotoxic effects of hypotonic (iopamidol) and isotonic (iodixanol) contract media (CMs) in vitro and in vivo. A total of 60 Wistar rats were included and were randomly divided into three groups (20 rats per group). Iodixanol (4 g iodine/kg), iopamidol (4 g iodine/kg) or equal volume of normal saline was injected via tail vein. HUVEC and H5V cell viability was determined by Cell Counting Kit‑8 agents. Western blotting was performed to detect ATP‑binding cassette subfamily G member 1 (ABCG1) expression. For histological analysis, hematoxylin and eosin staining was performed. Plasma endothelin, von Willebrand factor, tissue type plasminogen activator, plasminogen activator inhibitor, D‑Dimer, fibrinogen, anti‑thrombin III, plasminogen and nitric oxide synthase (NOS) were measured by using ELISA. Both iopamidol and iodixanol treatments deceased cell viability and increased apoptosis of HUVEC and H5V cells, along with downregulated NOS and ABCG1. The injection of iopamidol or iodixanol into rats changed the endothelium‑related plasma levels of biomarkers, including endothelin, von Willebrand factor, tissue type plasminogen activator, plasminogen activator inhibitor, D‑Dimer, fibrinogen and anti‑thrombin III. However, endothelia isolated from rat abdominal aorta in the iodixanol group retained their normal structure, whereas endothelial structure in the iopamidol group was injured and disrupted. The findings in the present study suggested that both hypotonic and isotonic CMs may lead to endothelial dysfunction and thrombin and fibrinolytic system disorder. However, hypotonic CMs may be more toxic than isotonic CMs. Therefore, additional cautions should be taken when selecting hypotonic CMs and their dosages during cardioangiography.


High-Speed 3D Printing of High-Performance Thermosetting Polymers via Two-Stage Curing.
Design and direct fabrication of high-performance thermosets and composites via 3D printing are highly desirable in engineering applications. Most 3D printed thermosetting polymers to date suffer from poor mechanical properties and low printing speed. Here, a novel ink for high-speed 3D printing of high-performance epoxy thermosets via a two-stage curing approach is presented. The ink containing photocurable resin and thermally curable epoxy resin is used for the digital light processing (DLP) 3D printing. After printing, the part is thermally cured at elevated temperature to yield an interpenetrating polymer network epoxy composite, whose mechanical properties are comparable to engineering epoxy. The printing speed is accelerated by the continuous liquid interface production assisted DLP 3D printing method, achieving a printing speed as high as 216 mm h-1 . It is also demonstrated that 3D printing structural electronics can be achieved by combining the 3D printed epoxy composites with infilled silver ink in the hollow channels. The new 3D printing method via two-stage curing combines the attributes of outstanding printing speed, high resolution, low volume shrinkage, and excellent mechanical properties, and provides a new avenue to fabricate 3D thermosetting composites with excellent mechanical properties and high efficiency toward high-performance and functional applications.


Retrospective review of rectal cancer surgery in northern Alberta.
Previous studies, including research published more than 10 years ago in Northern Alberta, have demonstrated improved outcomes with increased surgical volume and subspecialisation in the treatment of rectal cancer. We sought to examine contemporary rectal cancer care in the same region to determine whether practice patterns have changed and whether outcomes have improved. We reviewed the charts of all patients with rectal adenocarcinoma diagnosed between 1998 and 2003 who had a potentially curative resection. The main outcomes examined were 5-year local recurrence (LR) and disease-specific survival (DSS). Surgeons were classified into 3 groups according to training and volume, and we compared outcome measures among them. We also compared our results to those of the previous study from our region. We included 433 cases in the study. Subspecialty-trained colorectal surgeons performed 35% of all surgeries in our study compared to 16% in the previous study. The overall 5-year LR rate and DSS in our study were improved compared to the previous study. On multivariate analysis, the only factor associated with increased 5-year LR was presence of obstruction, and the factors associated with decreased 5-year DSS were high-volume noncolorectal surgeons, presence of obstruction and increased stage. Over the past 10 years, the long-term outcomes of treatment for rectal cancer have improved. We found that surgical subspecialization was associated with improved DSS but not LR. Increased surgical volume was not associated with LR or DSS.


Evidence for large inversion polymorphisms in the human genome from HapMap data.
Knowledge about structural variation in the human genome has grown tremendously in the past few years. However, inversions represent a class of structural variation that remains difficult to detect. We present a statistical method to identify large inversion polymorphisms using unusual Linkage Disequilibrium (LD) patterns from high-density SNP data. The method is designed to detect chromosomal segments that are inverted (in a majority of the chromosomes) in a population with respect to the reference human genome sequence. We demonstrate the power of this method to detect such inversion polymorphisms through simulations done using the HapMap data. Application of this method to the data from the first phase of the International HapMap project resulted in 176 candidate inversions ranging from 200 kb to several megabases in length. Our predicted inversions include an 800-kb polymorphic inversion at 7p22, a 1.1-Mb inversion at 16p12, and a novel 1.2-Mb inversion on chromosome 10 that is supported by the presence of two discordant fosmids. Analysis of the genomic sequence around inversion breakpoints showed that 11 predicted inversions are flanked by pairs of highly homologous repeats in the inverted orientation. In addition, for three candidate inversions, the inverted orientation is represented in the Celera genome assembly. Although the power of our method to detect inversions is restricted because of inherently noisy LD patterns in population data, inversions predicted by our method represent strong candidates for experimental validation and analysis.


Kinetic expression for maltose production from soluble starch by simultaneous use of beta-amylase and debranching enzymes.
The kinetics of the hydrolysis of soluble starch by simultaneous use of beta-amylase and either isoamylase or pullulanse was studied experimentally for a wide range of subtrate and enzyme concentrations. A kinetic expression was constituted for maltose production by beta-armylase, which was stimulated by an increase in linear linkage portions due to the debranching enzyme on amylopectin molecules. As a result, calculations by the kinetic expression agreed with time course data under various conditions.


Involvement of dopamine beta-hydroxylase in the neuroendocrine-immune regulatory network of white shrimp, Litopenaeus vannamei.
In shrimp, the biosynthesis of catecholamines, including dopamine and norepinephrine, is required for physiological and immunological responses against stress. Dopamine beta-hydroxylase (DBH), a copper-containing monooxygenase enzyme that plays an important role in catecholamine synthesis of the neuroendocrine regulatory network, was identified in Litopenaeus vannamei. In the present study, the potential role of DBH in the immunocompetence of L. vannamei was further estimated by depleting DBH by pharmaceutical inhibition of disulfiram and a gene silencing technique of L. vannamei DBH-double-stranded (ds)RNA (LvDBH-dsRNA). Immunocompetence was evaluated following the determination of the total hemocyte count, differential hemocyte count, phenoloxidase activity, respiratory bursts, superoxide dismutase activity, phagocytic activity, and the clearance efficiency as well as the susceptibility against Vibrio alginolyticus infection. At 30-120 min after shrimp had received disulfiram, they exhibited significantly reduced total hemocyte count, phenoloxidase activity of hemocytes in hemolymph, respiratory bursts of hemocytes in hemolymph and per hemocyte, phagocytic activity, clearance efficiency, and survival ratio against V. alginolyticus infection, compared to those injected with saline. In addition, the significantly lower total hemocyte count, phagocytic activity, clearance efficiency, and resistance to V. alginolyticus infection were observed in shrimp that received LvDBH-dsRNA at 3 days post injection compared to those injected with diethyl pyrocarbonate-water or non-targeting gene-dsRNA. The DBH depleted L. vannamei revealed immunosuppression and decreased the survival ratio to V. alginolyticus infection, which indicated that DBH played a crucial role in the neuroendocrine-immune regulatory network.


From the Eye of the Storm: Multi-Institutional Practical Perspectives on Neuroradiology from the COVID-19 Outbreak in New York City.
During the Severe Acute Respiratory Syndrome Coronavirus 2 (COVID-19) pandemic, neuroradiology practices have experienced a paradigm shift in practice, which affected everything from staffing, workflow, work volumes, conferences, resident and fellowship education, and research. This article highlights adaptive strategies that were undertaken at the epicenter of the outbreak in New York City during the past 4-6 weeks, as experienced by 5 large neuroradiology academic departments.


Skeleton photoperiods alter delayed-type hypersensitivity responses and reproductive function of Siberian hamsters (Phodopus sungorus).
Photoperiod (day length) can modulate immune function. Whether these photoperiodic effects on immune function are mediated directly by a circadian photoperiodic time measurement system or indirectly by nonspecific (e.g. stressful) effects of light is unknown. To discriminate between these two possibilities, Siberian hamsters (Phodopus sungorus) were housed in either long or short photoperiods (LD 16 : 8 h or LD 8 : 16 h) or in 'skeleton' long or short photoperiods (LD 1 : 14 h: LD 1 : 8 h or LD 1 : 6 h: LD 1 : 16 h). In the skeleton photoperiods, both long- and short-day animals received 2 h of light per day. After 10 weeks in their respective photoperiods, hamsters were tested for an antigen specific immune response using a delayed type hypersensitivity (DTH) model. Reproductive and endocrine responses of hamsters in each of the skeleton photoperiods were equivalent to those in standard long or short days, respectively. Hamsters in skeleton short days and LD 8 : 16 increased DTH responses compared to hamsters in both long-day groups. DTH responses were equivalent in both long-day groups. These results suggest that the influences of day length on immune function potentially are due to circadian photoperiodic time measurement systems.